Investigating the antigenic ligands for autoreactive T cells has been a high priority research goal for T1D because identification of peptide targets will lead to a better understanding of how this autoimmune disease develops and how it might be regulated. Insulin has long been considered to be the most important beta cell autoantigen in type 1 diabetes (T1D), but we recently discovered that two other secretory granule proteins, chromogranin A (ChgA) and islet amyloid polypeptide (IAPP), are also the source of antigenic peptides for autoreactive CD4 T cells. The goals of the first five-year period of this project were focused on identification of antigens for a panel of pathogenic CD4 T cell clones, whether post-translational modification (PTM) was involved in peptide antigenicity, and whether antigenic peptides could be used in strategies to induce antigen-specific tolerance. Our progress with all of these objectives has been significant, but our most notable discovery has been the identification of a novel PTM occurring in islet ?-cells and leading to the formation of hybrid peptides between fragments of insulin and sequences from other secretory granule protein cleavage products. Two of these hybrid insulin peptides (HIPs) have been demonstrated to be highly antigenic for different subsets of T cell clones from our panel, those that are ChgA-reactive and another set that is IAPP-reactive. Our hypothesis in the second five-year period of this project is that the target ligands for autoreactive CD4 T cells are HIPs.
Our aims will be to (1) define the role of HIP-reactive CD4 T cells in pathogenesis versus prevention of disease in NOD mice; (2) establish the presence of hybrid peptides in human islet beta cells; and (3) detect and characterize HIP-reactive T cells in human T1D patients and controls. The long-term translational significance of these studies lies in the potential for new reagents that could specifically detect autoreactive T cells as biomarkers of autoimmune diabetes in humans and/or serve as peptides for induction of antigen-specific tolerance.

Public Health Relevance

Hybrid peptides as Antigens for Diabetogenic CD4 T cells Project Narrative: Defining the autoantigens that drive the T cell mediated inflammatory response in type 1 diabetes (T1D) is necessary not only for understanding the disease process but is also critical for development of better approaches to diagnosis and therapy. Post-translational modification (PTM) of proteins is a common mechanism for the generation of peptides that are autoantigenic, but PTM in T1D has been little characterized. We have discovered a novel PTM in the pancreatic beta cells consisting of hybrid peptides between sequences of insulin and sequences from other secretory granule peptides. This project is to define the functional role of these hybrid insulin peptides and determine how they influence the T cell repertoire in T1D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Sechi, Salvatore
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University of Colorado Denver
Schools of Medicine
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Baker, Rocky L; Jamison, Braxton L; Wiles, Timothy A et al. (2018) CD4 T Cells Reactive to Hybrid Insulin Peptides Are Indicators of Disease Activity in the NOD Mouse. Diabetes 67:1836-1846
Wiles, Timothy A; Delong, Thomas; Baker, Rocky L et al. (2017) An insulin-IAPP hybrid peptide is an endogenous antigen for CD4 T cells in the non-obese diabetic mouse. J Autoimmun 78:11-18
Babon, Jenny Aurielle B; DeNicola, Megan E; Blodgett, David M et al. (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22:1482-1487
Baker, Rocky L; Bradley, Brenda; Wiles, Timothy A et al. (2016) Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes. J Immunol 196:39-43
Delong, Thomas; Wiles, Timothy A; Baker, Rocky L et al. (2016) Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351:711-4
Lindsay, Robin S; Corbin, Kaitlin; Mahne, Ashley et al. (2015) Antigen recognition in the islets changes with progression of autoimmune islet infiltration. J Immunol 194:522-30
Gottlieb, Peter A; Delong, Thomas; Baker, Rocky L et al. (2014) Chromogranin A is a T cell antigen in human type 1 diabetes. J Autoimmun 50:38-41
Cordova, Kristen N; Willis, Van C; Haskins, Kathryn et al. (2013) A citrullinated fibrinogen-specific T cell line enhances autoimmune arthritis in a mouse model of rheumatoid arthritis. J Immunol 190:1457-65
Baker, Rocky L; Delong, Thomas; Barbour, Gene et al. (2013) Cutting edge: CD4 T cells reactive to an islet amyloid polypeptide peptide accumulate in the pancreas and contribute to disease pathogenesis in nonobese diabetic mice. J Immunol 191:3990-4
Reisdorph, N; Wechsler, M E (2013) Utilizing metabolomics to distinguish asthma phenotypes: strategies and clinical implications. Allergy 68:959-62

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